Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a type of subtilisin protease with pre-protein convertase activity. PCSK9 is mainly expressed in the liver, the small intestine, and the kidney, yet little in the skin and the nervous system. PCSK9, which is secreted from liver to the blood circulation, can decrease the number of low-density lipoprotein (LDL) receptor (LDLR) on the cell surface through binding and endocytosis. Since LDLR can effectively eliminate LDL in the plasma, less LDLR will promote accumulation of LDL. Therefore, reduced LDLR mediated by PCSK9 will result in an increase in LDL cholesterol (LDL-C). PCSK9 also takes part in lipid metabolism of apolipoprotein B. Secretion of PCSK9 could elevate the triglyceride (TG) level in the gut followed by high hypercholesterolemia (Rashid S., et al., Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms. Circulation. 2014 Jul. 29; 130(5): 431-41.).
About 29% of patients with hypercholesterolemia are taking statins. However, 8.2% of patients with hypercholesterolemia are intolerant to statins or could not achieve the desired concentration of cholesterol with statins. It was estimated that a total of 390 million patients with hypercholesterolemia live in the top 7 largest pharmaceutical markets, not including china. According to the report “Investigation of nutrition and health status of Chinese Residents” released by the Ministry of Health on Oct. 12, 2004, 18.8% of adults in China have hypertension, a total of 160 million patients in the entire country, 70 million more than in 1991. The number of dyslipidemia patients has reached 160 million as well.
Currently, it is essential to develop novel immunotherapy antibodies, which can specifically bind to PCSK9 and block the association of PCSK9 and LDLR, which in turn will upregulate LDLR expression on the cell surface, enhance metabolism of LDL and cholesterol, and prevent and treat cardiovascular diseases caused by hypercholesterolemia. Furthermore, it is essential to develop highly effective PSCK9 antibody to enhance the metabolism of TG or to reduce TG level, with long term efficacy.